Mini-Symposium - Inhaled Corticosteroids Safety PanelInhaled corticosteroids: Effects on growth and bone health
Introduction
Slowed growth and reduction in bone mineral density (BMD) are known adverse effects of systemic exposure to corticosteroids. Studies have found systemic effects of oral corticosteroids on growth,[1], [2], [3] BMD,4 and risk of fracture.5 Systemic exposure is reduced when corticosteroids are inhaled instead of taken orally or parenterally. However, although asthma treatment and management guidelines recommend inhaled corticosteroids (ICSs) as the preferred first-line therapy for asthma,[6], [7] uncertainty remains among some clinicians about the extent of systemic effects among ICSs. In this article, we discuss the data on ICS systemic effects on growth and bone health.
The effects of ICSs on growth in children and bone health have been extensively reviewed in the past, and several recent reviews[8], [9], [10], [11] summarize this area very well. However, some clinicians who do not treat patients with asthma on a regular basis, for example, practitioners in primary care or pediatrics, are uncertain of the balance between ICS efficacy and safety. This article is one in a series of articles in a minisymposium entitled Inhaled Corticosteroids in Asthma: The Balance Between Safety and Efficacy, which was developed to help guide clinicians through identified knowledge and practice gaps concerning the balance of ICS efficacy and safety, the effects of ICS delivery and devices, and the importance of patient education and effective communication. As such, the goal of this article is not to comprehensively review all growth and bone health studies but to highlight key articles for clinicians who might not be familiar with the literature. This article focuses on key, well-designed studies of particular populations of interest. In particular, this review focuses on well-designed growth studies funded by the National Institutes of Health (NIH) and pharmaceutical industry after issuance of guidance by the US Food and Drug Administration (FDA).
Systemic availability varies among ICSs and depends on an ICS's pharmacokinetics, formulation, and delivery.11 These effects are discussed in more detail in 2 other articles in this minisymposium (Inhaled Corticosteroids: Ocular Safety and The HPA Axis and Inhalation Devices, Delivery Systems, and Patient Technique). Factors such as receptor-binding affinity, lipid conjugation, protein binding, and clearance from systemic circulation contribute to systemic adverse effects.11 In addition, drug formulation can affect the proportion of the ICS dose that is delivered to the lungs and systemic availability. In particular, in pressurized metered-dose inhalers (pMDIs), hydrofluoroalkane solution formulations deliver a higher fraction of smaller particles to the distal airways and distribute the drug more evenly throughout the lungs compared with chlorofluorocarbon formulations.12 The type of device can also affect systemic availability. Evidence suggests that compared with dry powder inhalers (DPIs), pMDIs may enhance lung deposition while reducing systemic bioavailability via the gastrointestinal tract.[13], [14] Note that the major source of systemic bioavailability of ICSs is the lung and not the gastrointestinal tract.15 In addition, ICS bioavailability is affected by the choice of spacers and masks.[16], [17] Nebulizers also affect bioavailability, as shown in one of the few growth studies in which an ICS was delivered by nebulizer.18
Section snippets
Growth in Children
A frequently expressed concern of ICSs is the systemic effects on growth in children. Growth is considered the most sensitive indicator of systemic corticosteroid activity by the FDA—more sensitive than the hypothalamic-pituitary-adrenal axis.19 However, detecting effects on growth is confounded by growth rates that vary throughout childhood. Our focus is on high-quality, well-designed studies with treatment durations of approximately 1 year or longer. These include NIH-funded studies that
Bone Health
ICSs also have systemic effects on bone health. Glucocorticoids cause reduced bone formation and increased bone resorption, which in turn decrease bone mass.33 Bone mass increases during childhood, peaking between 20 and 40 years of age.34 After the age of approximately 30 years, bone mass gradually decreases. Corticosteroid use can affect both the increase in bone mass in children and the rate of bone mass loss in adults. For adults, the main concerns of corticosteroid use are osteoporosis and
Conclusions
Low doses of systemically active ICSs can suppress growth and permanently affect the adult height of children with mild or moderate persistent asthma. The effect on adult height is on the order of 1 to 1.5 cm. Although this effect on growth should not stop us from using ICSs for asthma, it should be part of shared decision making among the child, the parent, and the physician. ICSs differ in their levels of systemic activity, and some ICSs, even at the highest recommended dose, have no
Acknowledgments
Thanks to Dr Rohit Katial for organizing the discussion panel and the panelists for their invigorating discussion and to Elise Eller, PhD, for her assistance in preparing this article. The National Jewish Health Office of Professional Education, particularly Matthew Stern and Andrea Harshman, MHA, CHCP, were instrumental in the development of this article.
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Cited by (33)
Is This Medication Safe for My Child? How to Discuss Safety of Commonly Used Medications With Parents
2022, Journal of Allergy and Clinical Immunology: In PracticeCitation Excerpt :The OTC switch for INCS, which suppress childhood growth, creates obvious and unique challenges for physicians who manage children taking OTC INCS. The ICS can also reduce BMD39–45 and were shown to contribute to the development of glaucoma and cataracts in most, but not all, studies.42,43 Only a few studies have examined the effect of topical CS for AD on short-term lower leg growth rate and produced conflicting results.44–46
Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum
2021, Neurobiology of DiseaseCitation Excerpt :Additionally, CIC does not appear to cause unwanted systemic adverse effects often observed with other systemic or inhaled sGCs, such as adrenal suppression, reduced long bone growth, or neurologic impairment. In fact, CIC has been used successfully in children as young as 6 years old as an alternative asthma therapy to current first-line agents to reverse adrenal suppression while still controlling respiratory symptoms (Liddell et al., 2017; Pedersen et al., 2006; Pedersen et al., 2010; Skoner, 2016). Given the potential for serious systemic side effects following neonatal sGC administration, alternative GR-targeting drugs for BPD treatment need to be evaluated, particularly those drugs with potential to limit adverse effects in the brain.
Tectochrysin ameliorates murine allergic airway inflammation by suppressing Th2 response and oxidative stress
2021, European Journal of PharmacologyCitation Excerpt :Clinically, inhalation of corticosteroids is used to control airway inflammation and immune response, and thus respiratory symptoms. However, both higher daily dose and larger cumulative dose are associated with increased bone density loss (Skoner, 2016), tracheobronchomalacia (Husta et al., 2017), increased risk of pneumonia (Kim et al., 2019), and insensitivity to corticosteroids (Prodanovic et al., 2018), indicating a requirement for novel therapeutic strategies. Asthma is initiated by Th2-dominated responses with elevated levels of Th2 cytokines, such as interleukin (IL)-4, IL-5 and IL-13.
Inhaled Corticosteroids and Endocrine Effects in Childhood
2020, Endocrinology and Metabolism Clinics of North AmericaCitation Excerpt :At higher ICS doses, however, differences in BMD were seen; compared with children treated with 400 μg/d to 800 μg/d, children receiving greater than 800 μg/d of ICS had significantly lower lumbar spine BMD (mean difference −0.05 g/cm2; 95% CI, −0.02 to −0.09). Thus, current consensus is that decreased BMD acquisition in children is associated with high doses but not low to medium doses of ICSs.44 Use of rescue ICS therapy only during asthma exacerbations theoretically would reduce the risk of adverse effects on BMD.
Bone Health in Women
2018, Primary Care - Clinics in Office PracticeMeasurement of fractional exhaled nitric oxide in real-world clinical practice alters asthma treatment decisions
2018, Annals of Allergy, Asthma and ImmunologyCitation Excerpt :Alternatively, low FeNO values can suggest the absence of corticosteroid-sensitive type 2 inflammation or a misdiagnosis of asthma. Unnecessary exposure of patients to corticosteroids increases the likelihood of adverse effects associated with these medications.41–44 Smith et al26 found that FeNO measurement allowed maintenance doses of ICS to be significantly decreased without compromising asthma control compared with dose adjustments based on conventional guidelines.
Disclosures: Dr Skoner declares that he has received grant and research support from Genentech, GlaxoSmithKline, Greer, Merck, Novartis, Sunovion, and Teva. Dr Skoner is a consultant for Greer, Meda, Merck, Mylan, Sunovion, and Teva. He also states that he is on a speaker's bureau for Greer, Genentech, Meda, Merck, Novartis, and Sunovion.
Funding Sources: This article was supported by an independent educational grant from Meda Pharmaceuticals Inc.